The present invention is concerned with novel mGluR antagonists, methods of their synthesis and the treatment and/or prevention of neurological disorders.
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter sent out by a neuron, with a neuroreceptor on another neuron.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluRs are known and some of these even have sub-types. On the basis of structural parameters, the different second messenger signaling pathways and their different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands, particularly antagonists, of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington""s chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, psychoses, anxiety, vomiting, dyskinesia and depression.
It is an object of the present invention to provide pharmaceutically active substances, medicaments and a method of their manufacture for the control or prevention of illnesses of the aforementioned kind. It is another object to provide radiolabeled mGluR1 receptor antagonists for use in binding assays.
It has surprisingly been found that the compounds of formula I are antagonists of metabotropic glutamate receptors of the first group: 
wherein
R1 signifies oxygen, hydroxy, lower alkoxy or 2,2,2-trifluoroethoxy;
R2 signifies nitro or cyano;
R3 signifies hydrogen, lower alkyl, oxygen, lower alkoxy, amino, lower alkyl-amino or hydroxy-lower alkyl-amino;
R4 signifies hydrogen, lower alkyl, lower alkenyl, or is absent, if the adjacent nitrogen atom already is the origin of three bonds as xe2x80x94Nxe2x95x90 or xe2x95x90Nxe2x80x94;
R5, R6, R9 and R10 signify, independently from each other, hydrogen or lower alkyl; 
R7, R8, R11 or R12 signify, independently from each other, hydrogen, lower alkyl, or hydroxy;
R13 and R14 signify, independently from each other, hydrogen or lower alkyl;
R15 and R16 signify, independently from each other, hydrogen or lower alkyl;
R17 signifies hydrogen, lower alkyl, lower alkoxy, hydroxy or amino;
R18 signifies hydrogen or hydroxy;
R19 signifies hydrogen, lower alkyl, lower alkoxy, hydroxy or amino;
V signifies NH, S or O; and
the dotted line may be a bond,
as well as with their pharmaceutically acceptable salts in their racemic and optically active form.
The present invention encompasses compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments. Furthermore, the use of radiolabeled mGluR1 receptor antagonists of formula I in a binding assay is also encompassed by the present invention.
The present invention is further illustrated by the following descriptions of preferred embodiments and examples. These preferred embodiments and examples are not limiting on the invention. One of skill in the arts of organic synthesis and/or pharmaceutical chemistry would well recognize a variety of obvious variations to these preferred embodiments and examples which would still be encompassed by this invention. The invention is limited only by the claims that follow and their equivalents.
Compounds of formula Ixe2x80x2
wherein
R1 is oxygen, hydroxy, lower alkoxy or 2,2,2-trifluoroethoxy;
R2 is nitro or cyano;
R3 is hydrogen, lower alkyl, oxygen, lower alkoxy, amino, lower alkyl-amino or hydroxy-lower alkyl-amino;
R4 is hydrogen, lower alkyl, lower alkenyl or is absent, if the adjacent nitrogen atom is part of a covalent double bond;
R5, R6, R9 and R10 are, independently from each other, hydrogen or lower alkyl; 
xe2x80x83is selected from the group consisting of 
xe2x80x83wherein
R7, R8, R11 or R12 are, independently from each other, hydrogen, lower alkyl, or hydroxy;
R13 and R14 are, independently from each other, hydrogen or lower alkyl;
R15 and R16 are, independently from each other, hydrogen or lower alkyl;
R17 is hydrogen, lower alkyl, lower alkoxcy, hydroxy or amino;
R18 is hydrogen or hydroxy;
R19 is hydrogen, lower alkyl, lower alkoxy, hydroxy or amino;
V is NH, S or O; and
a dotted line is an optional bond,
and pharmaceutically acceptable salts of a compound of formula Ixe2x80x2 are antagonists of mGluR.
Formula Ixe2x80x2 defines the same set of compounds as formula I. The compounds encompassed by Formula Ixe2x80x2 may be sub-divided into compounds of formulas Ixe2x80x2a, Ixe2x80x2b and Ixe2x80x2c: 
wherein
R1xe2x80x2 is hydroxy, lower alkoxy or 2,2,2-trifluoroethoxy;
R3xe2x80x2 is hydrogen, lower alkyl, lower alkoxy, amino, lower alkyl-amino or hydroxy-lower alkyl-amino;
R4xe2x80x2 is hydrogen, lower alkyl or lower alkenyl; and
R2, R5, R6, R9, R10 and 
xe2x80x83are as defined for formula Ixe2x80x2.
Preferred compounds of formulas I, Ixe2x80x2, Ixe2x80x2a, Ixe2x80x2b and Ixe2x80x2c in the scope of the present invention are those in which R2 is NO2.
Further preferred are compounds of formula I in the scope of the present invention,
wherein
R1 is xe2x95x90O or lower alkoxy and
HET represents a thiophene group.
The following are examples of such compounds:
[rac]-6-(4-Hydroxy-4,5,7,8-tetrahydro-thieno[2,3-d] azepin-6-yl)-2-methyl-5-nitro-3H-pyrimidin-4-one,
2-Methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-3H-pyrimidin-4-one,
6-(6-Ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine, or
3-Ethyl-2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno [2,3-d] azepin-6-yl)-3H-pyrimidin-4-one.
Also preferred are compounds of formula I in the scope of the present invention,
wherein
R1 is xe2x95x90O or lower alkoxy, and
HET represents a thiazole group.
The following are examples of such compounds:
2-Methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one,
6-(6-Ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine,
3-Ethyl-2-methyl-6-(2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-5-nitro-3H-pyrimidin-4-one,
6-(2-Amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl) -2-methyl-5-nitro-3H-pyrimidin-4-one,
6-(2-Amino-4,5,7,8-tetrahydro-thiazolo [4,5-d]azepin-6-yl)-3-ethyl-2-methyl-5-nitro-3H-pyrimidin-4-one, or
2-Methyl-5-nitro-6-(4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-3H-pyrimidin-4-one.
Further preferred compounds of formula I in the scope of the present invention are those, in which
R1 is hydroxy and
HET represents a pyrimidine group.
The following are examples of such compounds:
7-(6-Hydroxy-2-methyl-5-nitro-pyrimidin-4-yl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol, or
2-Methyl-5-nitro-6-(5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl)-pyrimidin-4-ol.
The term xe2x80x9clower alkylxe2x80x9d used in thee present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term xe2x80x9clower alkenylxe2x80x9d used in the present description denotes straight-chain or branched unsaturated hydrocarbon residues with 2-7 carbon atoms, preferably with 2-4 carbon atoms.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d denotes conventional acid-addition salts or base-addition salts which retain the biological effectiveness and propertied of the compounds of formulae I, Ixe2x80x2, Ixe2x80x2a, Ixe2x80x2b and/or Ixe2x80x2c and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methane-sulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured by
reacting a compound of the formula 
with a compound of formula 
to a compound of formula 
wherein R3 and R5 to R12 have the significance given above.
reacting a compound of formula 
to a compound of formula 
or to a compound of formula 
wherein R2, R3 and R5 to R12 have the significance given above and R signifies hydrogen or lower alkyl, or
reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein the substituents have the significance given above, and, if desired,
converting a functional group in a compound of formula I into another functional group and, if desired,
converting a compound of formula I into a pharmaceutically acceptable salt. The conversion of one functional group into another functional group and the formation and isolation of pharmaceutically acceptable salts can each be carried out according to methods known in the art.
In the following schemes I to VII and in Examples 1-10 the reaction steps and reaction variants a)-c) are described in more detail.
Chloro-methoxy-nitro pyrimidines VII (Scheme I) are known [e.g. 6-chloro-4-methoxy-2-methyl-5-nitro-pyrimidine: Helv. (1958), 41, 1806]. Treatment of the 2-alkyl 6-chloro-4-methoxy-5-nitro-pyrimidines VII with hydrobromic acid in acetic acid preferentially at temperatures between 0xc2x0 C. and 60xc2x0 C. gives the 2-alkyl-6-bromo-5-nitro-3H-pyrimidin-4-ones III (Scheme I). 
The 2-alkyl-6-bromo-5-nitro-3H-pyrimidin-4-ones III react with optionally substituted secondary amines IV in the presence of a base like triethylamine in solvents like N,N-dimethylformamide, dimethylsulfoxide, acetone, methyl-ethylketone or tetrahydrofuran at temperatures between 0xc2x0 C. and 100xc2x0 C. to the tertiary amines I-1 (Scheme II). A method of preparing an optionally substituted secondary amines according to formula IV is exemplified in the Examples found below, and one of skill in the art of organic synthesis would be able to form other compounds according to formula IV from this example and their knowledge of the art. 
Bis(methylthio)-acrylates VIII react with optionally substituted secondary amines IV in the presence of bases like potassium carbonate and/or triethylamine in solvents like ethanol, methanol, acetone or methyl-ethylketone at temperatures between room temperature and 100xc2x0 C. to adducts V, which can be formed as Z-isomer, as mixture of E and Z isomers or as E isomer (Scheme III). Bis(methylthio)-acrylates are well known in the chemical literature and many are commercially available; e.g. ethyl 2-cyano-3,3-bis(methylthio)acrylate is commercially avialable from TCI America. Adducts V can be reacted with amidines, urea or thiourea derivatives VI and VIa either in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (commercially available from suppliers like Aldrich and Fluka) in N,N-dimethylformamide or dimethylsulfoxide at temperatures between 70xc2x0 C. and 140xc2x0 C. or in the presence of sodium ethylate in ethanol preferentially at reflux thus yielding pyrimidineoles I-2 or pyrimidinones 1-3. 
Alkylation of adducts I-2 with R2 being a cyano or a nitro group (Scheme III) using optionally substituted alkyl halides, tosylates, mesylates or trifluoro-methanesulfonates in solvents like ethanol, methanol, dichloromethane, chloroform, N,N-dimethylformamide, dimethylsulfoxide, acetone, methyl-ethylketone or tetrahydrofuran in the presence of a base like alkali carbonates, e.g. sodium, potassium or cesium carbonate, tertiary amines like triethylamine or ethyl-diisopropylamine, alkali methyl hydrides, like sodium or potassium hydride, or phase transfer catalysts like benzyl-trimethylammonium chloride in the presence of solid or concentrated aqueous sodium hydroxide gives variable mixtures of N-and/or O-alkylated products I-3 and I-4.
Azepines IV-1 condensed to a heteroaromatic 5-membered ring bearing two heteroatoms can be prepared from bromoazepinones IX (Scheme IV) as e.g. 4-bromo-5-oxo-azepane-1-carboxylic acid tert.-butyl ester (prepared from 5-bromo-azepan-4-one hydrobromide (1:1) [Ger. Offen. (1989), DE 3820775] with di-tert.-butyldicarbonate in dioxane/aq. sodium hydrogen carbonate solution at room temperature) by reaction with an amide, a thioamide, an urea or a thiourea compound X in a solvent like ethanol, dioxane or acetonitrile in the presence of a base like sodium ethylate or triethylamine at temperatures between room temperature and 120xc2x0 C. followed by removal of the tert.-butoxy carbonyl function with acid, e.g. with hydrogen chloride (aqueous, 37%) in methanol at temperatures between room temperature and 80xc2x0 C. Other species of bromoazepinones IX can be prepared by one of skill in the art of organic synthesis by analogy with knowledge well-known in the art. 
Azepines IV-2 condensed to a heteroaromatic 6-membered ring bearing two heteroatoms can be prepared from alkoxycarbonyl-azepinones XII as e.g. 4-ethoxy-carbonyl-5-oxo-azepane-1-carboxylic acid tert.-butyl ester [Synthetic Communications 22 (1992), 1249-1258] (Scheme V) by condensation with an amidine XIII in a solvent like ethanol, dioxane or N,N-dimethylformamide in the presence of a base like sodium ethoxide or potassium tert.-butylate at temperatures between 40xc2x0 C. and 110xc2x0 C. Other species of alkoxycarbonyl-azepinones XII can be prepared by one of skill in the art of organic synthesis by analogy with knowledge well-known in the art. The primarily formed compounds XIVa can be further modified by transformation of the hydroxy function into a leaving group, e.g. a trifluorosulfonyloxy function with trifluorosulfonic acid anhydride and a base like triethylamine in an inert solvent like dichloromethane at temperatures between xe2x88x9240xc2x0 C. and 60xc2x0 C., thus giving compounds XIVb. The trifluorosulfonyloxy function in compounds XIVb can then be replaced by a hydrazine moiety by reacting it with hydrazine in a solvent like ethanol preferentially at reflux giving compounds XIVc. Hydrazino-compounds XIVc can be transformed by silver oxide in ethanol at reflux into the compounds XIVd, a sequence as described in [Bull. Chem. Soc. Jap. (1971), 44(1), 153-8]. Removal of the tert.-butoxy carbonyl function in compounds XIVa or XIVd with acid, e.g. with hydrogen chloride (aqueous, 37%) in methanol at temperatures between room temperature and 80xc2x0 C. gives then the azepines IV-2. 
5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepines IV-3 and IV-5 with or without a hydroxy function at the carbon attached to the thieno moiety are known [J. Heterocyclic Chem. 22, 1011 (1985)]. Precursor acid chlorides XV [J. Heterocyclic Chem. 22, 1011 (1985)] bearing preferentially a tosyloxy protective function at the azepine secondary nitrogen function are cyclized in an inert solvent like 1,2-dichloroethane, dichloromethane or nitrobenzene in the presence of a Lewis acid catalyst like aluminium trichloride, tin tetrachloride or phosphorous pentachloride at temperatures between xe2x88x9240xc2x0 C. and 80xc2x0 C. to yield the protected ketones XVI. Keto thieno[2,3-d]azepines IV-4 are then prepared by cleavage of N-tosyl function with hydrobromic acid in the presence of a scavenger reagent like phenol in a solvent like ethyl acetate at room temperature, whereas hydroxy thieno[2,3-d]azepines IV-3 can be obtained by simultaneous reduction of the keton function and removal of the N-tosyl protective function by treatment with sodium bis(methoxyethoxy)aluminium-hydride in toluene at reflux. The hydroxy thieno[2,3-d]azepines IV-3 can be further reduced to 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepines IV-5 with stannous chloride in acetic acid in the presence of hydrochloric acid at temperatures between room temperature and 100xc2x0 C.
5,6,7,8-Tetrahydro-4H-thieno[3,4-d]azepines IV-6 isomeric to 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepines IV-5 can be prepared from 2-thiophen-3-yl-ethylamine derivatives XVII [Eur. Pat. Appl. (1988), EP 274324 A1] in an analogous sequence as described for the thieno[2,3-d]azepines outlined in detail in Scheme VI. 
A labeled compound, for example 1-ethyl-2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile, is needed for the binding assay for the characterization of mGluR 1 antagonistic properties and can be prepared according to synthesis schemes I-III starting from a labeled amine as the 1,1,2-tritritio-2,3,4,5-tetrahydro-1H-benzo[d]azepine XXI which can be prepared as outlined in Scheme VII. The 1-(5-bromo-1,2-dihydro-benzo[d]azepin-3-yl)-ethanone XIX can be obtained by reaction of the 1-(1,2,4,5-tetrahydro-benzo [d]azepin-3-yl)-ethanone XVIII [J. Heterocyci. Chem. (1971), 8(5), 779-83] with N-bromosuccinimide in carbon tetrachloride in the presence of a radical initiator like dibenzoylperoxide or 1,1xe2x80x2-azobis-(cyclohexanecarbonitrile) preferentially at reflux. Hydrogenation of the 1-(5-bromo-1,2-dihydro-benzo[d]azepin-3-yl)-ethanone XIX with tritium gas using a palladium or platinum catalyst in solvents methanol, ethanol or an ether like tetrahydrofuiran preferentially in the presence of a base like triethylamine gives the 1-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone XX which can be converted into the 1-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone XXI with conc. aq. hydrochloric acid in methanol. 
The pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation of pharmaceutically acceptable salts of acidic compounds of formula I.
The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor antagonists and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders, memory deficits and psychosis. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington""s chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
The compounds of the present invention are group I mGluR antagonists and were tested using the following method:
Binding assay with tritiated 1-ethyl-2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile: HEK 293 cells were transiently transfected with the rat mGluR1a receptor. The cells were collected and washed 3 times with PBS. The cell pellets were frozen at xe2x88x9280xc2x0 C. Membranes were prepared from HEK 293 cells transfected with the rat mGluR1a receptor and used in the binding experiments at 10 xcexcg proteins per assay after resuspension in a HEPES NaOH 20 mM, pH=7.4 binding buffer. 1-Ethyl-2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile (S.A. 33.4 Ci/mmol) was used at 3 nM final concentration. The incubation with variable concentrations of potential inhibitors was performed for 1 hour at room temperature, the incubate was then filtered onto GF/B glass fiber filter preincubated 1 hour in PEI 0,1% and washed 3 times with 1 ml of cold binding buffer. The radioactivity retained on the unifilter 96 was counted using a Topcount xcex2 counter. After correction for non specific binding the data were normalized and the IC50 value calculated using a 4 parameters logistic equation which was fitted to the inhibition curve.
Preferred compounds have an IC50 range of 0.001-50.00 xcexcM (B-IC50).
In the table below are shown some specific activity data of preferred compounds:
The compounds of formula I and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also encompassed by the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
Finally, as mentioned earlier, the use of compounds of formula I and of pharmaceutically acceptable salts thereof for the production of medicaments, especially for the control or prevention of acute and/or chronic neurological disorders of the aforementioned kind, is also apart of the invention.